Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy were used to evaluate the melanocortin-1 receptor (MC1R) gene, the major regulator of pigmentation in humans, and somatic mutations of the BRAF oncogene, involved in the MAP-kinase pathway of signal transduction in melanomas. In subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage, we found a strong association between MC1R germline variants and melanoma with somatic mutations in the BRAF oncogene. We plan to first verify this association and the role of potential modifiers in an independent population. Germline CDKN2A mutations have been observed in 20-40% of high-risk melanoma-prone families, however little is known about their prevalence in population-based cases and controls. Multiple MC1R variants have been associated with increased risk of melanoma. The Icelandic population has a high frequency of red hair and blond hair color subjects making it an ideal population to evaluate variation in MC1R.We resequenced the CDKN2A and MC1R genes in 703 registry-ascertained melanoma cases and 691 population-based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. Evaluation of associations is in progress.One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from North-Eastern Italy. When the sample size reaches 100 subjects, we plan to study the expression and presence of mutations in multiple genes of the cell cycle, telomere, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi.Relatives of 365 of the glioma cases from a DCEG comprehensive case-control study of adults with brain tumors were interviewed about personal/family medical history and other risk factors. Analyses to examine the risk of cancer among the first degree relatives compared to population controls have been completed. Examination of questionnaire data from a retrospective single institution study of childhood medulloblastoma showed little evidence for increased cancer risks among relatives of medulloblastoma patients.Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. We initiated a collaboration with the Department of Radiation Oncology, Massachusetts General Hospital, Boston, to try to identify chordoma families to help map and identify a chordoma susceptibility gene. The project involves obtaining personal and family medical history, buccal cells and slides of tumor tissue from the subgroup of patients most likely to have a genetic predisposition to chordoma: those diagnosed with chordoma <18 years. During the past year we completed enrollment of 45 chordoma patients. We are in the process of obtaining personal and family medical history, buccal cells and tumor tissue from them.In collaboration with Yale University Tissue Microarray (TMA) core facility, we have successfully built TMAs of 842 invasive tumors (TMA1) collected from the Polish Breast Cancer Study. We have immunohistochemically stained these TMAs for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways. Analyses of these markers suggest that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. We have also stained these arrays for four markers (ER-alpha, ER-beta, PR and HER2) using a newly developed Automated Quantitative Analysis (AQUA). Comparison of the two approaches (AQUA and IHC) for the same four markers demonstrated AQUA analyses of tumors represented in TMAs provide reliable, quantitative measures of marker expression. Recently, we built a new set of TMAs (TMA2) including 919 Polish breast cancer cases with three-fold redundancy. Combined, TMA1 and TMA2, have 1,500 invasive tumors with at least two-fold redundancy. We have stained the new arrays (TMA2) for all five molecular signature markers and the old arrays (TMA1) for CK5 and EGFR using AQUA, which gave us AQUA data for all five signature markers from a complete set of invasive breast cancer cases built on TMAs. We have also established a technique in constructing TMAs from non-invasive epithelial tissues (normal terminal duct lobular units [TDLUs] and ductal carcinoma in situ [DCIS]), and successfully built 32 TMA blocks of 1,547 tissue cores including both non-invasive (normal TDLUs [N=689] and DCIS [N=501]) tissues and their associated invasive tumors (N=357) collected from 560 Polish breast cancer cases. We have stained these non-invasive arrays with all five molecular signature markers and analysis is in process. Renal cell carcinoma (RCC) rates in Central and Eastern Europe are among the highest in the world. The von Hippel Lindau-Hypoxia Inducible Factor (VHL-HIF) pathway has been implicated in kidney cancer tumorigenesis. We investigated the role of common variants in genes in the VHLHIF pathway in the susceptibility of sporadic RCC and clear cell RCC. We identified common genetic variants in genes in the VHL-HIF pathway associated with kidney cancer risk. We plan to replicate the finding in additional study populations. Analyses of registry data from Sweden and Denmark are continuing. We conducted analyses of medical conditions associated with CLL and multiple myeloma (MM) and showed an increased risk for respiratory infections and both CLL and MM, suggesting that they may trigger a malignant process in susceptible individuals. We also demonstrated that family history of cancer increased risk of individuals with lymphoma to develop certain second cancers. We are conducting a new study using laboratory and population registry data from Sweden to quantify personal and familial associations of monoclonal gammopathy of uncertain significance (MGUS) with other LP tumors. Approximately 4500 MGUS cases were identified from all of the major hematologyoncology units in Sweden who had linkable relatives. Compared with controls, relative risk (RR) of MGUS was significantly increased in relatives of MGUS cases. Risks of MM, WM, and CLL were also increased. Risk-estimates were similar for parents, siblings, and offspring; the same was true when we estimated risks by age at MGUS of cases (above vs. below 65 yrs), and sex of relatives. There was no increased risk of NHL or HL among relatives of MGUS cases. Preliminary analyses of relatives of WM cases showed that they had a higher risk of MGUS, WM, and CLL but not MM. This supports our data from high risk families indicating a genetic association between certain MGUS subtypes, WM, and CLL. We have also begun to analyze myeloproliferative (MPD) malignancies including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) using similar methodology. Preliminary results indicate that the relative risks for developing any MPD in first degree relatives of MPD patients are highly elevated (RR=5.6, 95% CI, 3.8-8.2).